Bacterial infections pose a continuing medical problem because anti-bacterial drugs eventually engender resistance in the bacteria on which they are used. Consequently, a need exists for new drugs with efficacy against pathogenic bacteria for use in the therapy and prophylaxis of bacterial infections.
One target for development of anti-bacterial drugs has been dihydrofolate reductase (DHFR), an enzyme on the synthetic pathway to purine and pyrimidine nucleotides. DHFR inhibitors have been disclosed in US 20090118311, which is hereby incorporated by reference in its entirety.
Folate (pteroylglutamate) is a vitamin which is a key component in the biosynthesis of purine and pyrimidine nucleotides. Following absorption, dietary folate is reduced to dihydrofolate and then further reduced to tetrahydrofolate by the enzyme dihydrofolate reductase (DHFR). Inhibition of DHFR leads to a reduction in nucleotide biosynthesis resulting in inhibition of DNA biosynthesis and reduced cell division. DHFR inhibitors are widely used in the treatment of cancer, cell proliferative diseases such as rheumatoid arthritis, psoriasis and transplant rejection. DHFR inhibitors have also found use as anti-infective and anti-parasitic agents. Many types of DHFR inhibitor compounds have been suggested, and several such compounds are used as anti-cancer, anti-inflammatory, anti-infective and anti-parasitic agents.
Methotrexate is the most widely used DHFR inhibitor, which contains a glutamate functionality that enables it to be actively transported into and retained inside of cells. However, cancer cells can become resistant to methotrexate by modifying this active transport mechanism. Furthermore, non-mammalian cells lack the active transport system and methotrexate has limited utility as an anti-infective agent. Lipophilic DHFR inhibitors which can be taken up by passive diffusion into cells have therefore been developed both to circumvent cancer cell resistance and for use as anti-infective agents. However, agents that passively diffuse into cells also exit the cell readily. Thus, there remains a need in the art for DHFR inhibitors that accumulate in cells in a way that does not depend on the active transport mechanism of methotrexate or on the lipophilicities.